Structural Study of SARS-CoV-2 Antibodies Identifies a Broad-Spectrum Antibody That Neutralizes the Omicron Variant by Disassembling the Spike Trimer.
Structural Study of SARS-CoV-2 Antibodies Identifies a Broad-Spectrum Antibody That Neutralizes the Omicron Variant by Disassembling the Spike Trimer.
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SARS-CoV-2 抗体的结构研究鉴定出一种广谱抗体，可通过分解刺突三聚体来中和 Omicron 变体
DOI：
10.1128/jvi.00480-22
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发表时间：
2022-08-24
影响因子：
5.4
通讯作者：
Sun, Lei
中科院分区：
文献类型：
--
作者：
Zhan, Wuqiang;Tian, Xiaolong;Zhang, Xiang;Xing, Shenghui;Song, Wenping;Liu, Qianying;Hao, Aihua;Hu, Yuxia;Zhang, Meng;Ying, Tianlei;Chen, Zhenguo;Lan, Fei;Sun, Lei
新型严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）变体的不断出现，给抗击2019冠状病毒病（COVID-19）大流行带来了新的挑战。新出现的欧米克隆菌株引起了严重的免疫逃逸，在世界范围内引起了前所未有的关注。迫切需要开发一种针对保守和通用表位的抗体。在我们之前的研究中，从恢复期患者中分离出了一组针对COVID-19的中和抗体（nab）。在这项研究中，我们研究了这些nab对SARS-CoV-2关注变体（VOCs）的适应性，发现IgG 553-49可以中和SARS-CoV-2 Omicron变体的假病毒。此外，我们还测定了SARS-CoV-2刺突(S)蛋白与三种针对不同表位（553-49、553-15和553-60）的单克隆抗体复合物的冷冻电镜（cro - em）结构。值得注意的是，553-49靶向一个新的保守表位，并通过分解S三聚体来中和病毒。IgG 553-15是一种中和除Omicron外的所有VOCs的抗体，它将两个S三聚体交联形成三聚体，表明553-15通过位阻和病毒粒子聚集来中和病毒。这些发现表明，针对这一高度保守的表位开发553-49和其他抗体的潜力，有望成为COVID-19的治疗试剂。SARS-CoV-2的Omicron菌株的出现引起了更高的免疫逃逸，引发了对抗体治疗和疫苗有效性的前所未有的担忧。在这项研究中，我们鉴定了一种SARS-CoV-2中和抗体553-49，它通过靶向一个完全保守的新表位来中和所有变体。此外，我们发现IgG 553-15通过交联病毒粒子中和SARS-CoV-2，而553-60通过阻断受体结合发挥作用。不同受体结合域（RBD）表位的比较表明，553-49表位隐藏在S三聚体中，并在SARS-CoV-2的进化过程中保持高度保守，使553-49成为一种有希望的治疗试剂，用于治疗新出现的Omicron和未来的SARS-CoV-2变体。
The continuous emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses new challenges in the fight against the coronavirus disease 2019 (COVID-19) pandemic. The newly emerging Omicron strain caused serious immune escape and raised unprecedented concern all over the world. The development of an antibody targeting a conserved and universal epitope is urgently needed. A subset of neutralizing antibodies (NAbs) against COVID-19 from convalescent patients were isolated in our previous study. In this study, we investigated the accommodation of these NAbs to SARS-CoV-2 variants of concern (VOCs), revealing that IgG 553-49 neutralizes pseudovirus of the SARS-CoV-2 Omicron variant. In addition, we determined the cryo-electron microscopy (cryo-EM) structure of the SARS-CoV-2 spike (S) protein complexed with three monoclonal antibodies targeting different epitopes, including 553-49, 553-15, and 553-60. Notably, 553-49 targets a novel conserved epitope and neutralizes the virus by disassembling S trimers. IgG 553-15, an antibody that neutralizes all of the VOCs except Omicron, cross-links two S trimers to form a trimer dimer, demonstrating that 553-15 neutralizes the virus by steric hindrance and virion aggregation. These findings suggest the potential to develop 553-49 and other antibodies targeting this highly conserved epitope as promising therapeutic reagents for COVID-19. IMPORTANCE The emergence of the Omicron strain of SARS-CoV-2 caused higher immune escape, raising unprecedented concerns about the effectiveness of antibody therapies and vaccines. In this study, we identified a SARS-CoV-2 neutralizing antibody, 553-49, which neutralizes all variants by targeting a completely conserved novel epitope. In addition, we revealed that IgG 553-15 neutralizes SARS-CoV-2 by cross-linking virions and that 553-60 functions by blocking receptor binding. Comparison of different receptor binding domain (RBD) epitopes revealed that the 553-49 epitope is hidden in the S trimer and keeps a high degree of conservation during SARS-CoV-2 evolution, making 553-49 a promising therapeutic reagent against the emerging Omicron and future variants of SARS-CoV-2.
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64.5
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